Effectiveness of metyrapone in treating Cushing's syndrome: a retrospective multicenter study in 195 patients
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BACKGROUND: Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the steroidogenesis inhibitor metyrapone for this purpose. OBJECTIVE: The objective was to assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with CS. DESIGN: This was designed as a retrospective, multicenter study. SETTING: Thirteen University hospitals were studied. PATIENTS: We studied a total of 195 patients with proven CS: 115 Cushing's disease, 37 ectopic ACTH syndrome, 43 ACTH-independent disease (adrenocortical carcinoma 10, adrenal adenoma 30, and ACTH-independent adrenal hyperplasia 3). MEASUREMENTS: Measurements included biochemical parameters of activity of CS: mean serum cortisol "day-curve" (CDC) (target 150-300 nmol/L); 9 am serum cortisol; 24-hour urinary free cortisol (UFC). RESULTS: A total of 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L [26.2 μg/dL] vs 348.6 nmol/L [12.6 μg/dL]; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L [32.0 μg/dL] vs 491.1 nmol/L [17.8 μg/dL]; P < .0001); and UFC (37 patients, 1483 nmol/24 h [537 μg/24 h] vs 452.6 nmol/24 h [164 μg/24 h]; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 μg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 μg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible. CONCLUSIONS: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS.
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Mean UFC is routinely used in clinical practice and research to monitor disease control and treatment response in patients with CS treated with medical therapy.
“Mean UFC is routinely used in clinical practice and research to monitor disease control and treatment response in patients with CS treated with medical therapy (129-137).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [131]
The Materials and Methods (page unavailable) identify UFC as a monitoring test and say mean UFC values were compared before and during metyrapone treatment. This supports its use to assess treatment response in the study, but the Discussion says monitoring tests and their frequency varied; it does not establish that mean UFC is routinely used across clinical practice and research for all medical therapies for Cushing’s syndrome. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn clinical trials, the efficacy of steroidogenesis inhibitors and pituitary-directed therapies in patients with CS was primarily evaluated by normalization of cortisol secretion per UFC.
“In clinical trials, the efficacy of steroidogenesis inhibitors and pituitary-directed therapies in patients with CS was primarily evaluated by the normalization of cortisol secretion per UFC (129-137).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [131]
The Materials and Methods (page unavailable) define UFC below the assay’s upper limit of normal as one measure of biochemical control. But this was a retrospective metyrapone study, not a clinical trial; it also assessed serum cortisol day-curves and 9 am serum cortisol. It does not establish that trials of steroidogenesis inhibitors and pituitary-directed therapies primarily used UFC normalization. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe restoration of cortisol circadian rhythm following medical therapy has not been investigated or established for most medications used to treat CS, and it is not routinely measured to determine treatment response.
“The restoration of cortisol circadian rhythm following medical therapy has not been investigated or established for most medications used to treat CS, and it is not routinely measured to determine treatment response (129-137).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [131]
The Materials and Methods (page unavailable) say cortisol day-curves were not routinely performed before treatment and that treatment response was assessed using mean cortisol values, rather than restoration of a circadian rhythm. This supports the point about limited rhythm monitoring in this metyrapone study, but the paper does not establish whether rhythm restoration has been investigated for most medications used to treat Cushing’s syndrome or whether rhythm is routinely measured across those treatments. (LLM, conf=0.78)
Experimental — accuracy not yet measured
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Surgery and perioperative management of patients with Cushing's disease
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Iatrogenic adrenal insufficiency in adults
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Updates in the Medical Treatment of Pituitary Adenomas
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Individualized medical treatment options in Cushing disease
Gilis-Januszewska, A., Bogusławska, A., Rzepka, E., Ziaja, W., & Hubalewska-Dydejczyk, A. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1060884 · Cited by 31 · see citing works
Tumor Microenvironment in Adrenocortical Carcinoma: Barrier to Immunotherapy Success?
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Effectiveness of Medical Treatment of Cushing’s Disease: A Systematic Review and Meta-Analysis
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MRI–Negative Cushing's Disease: A Review on Therapeutic Management
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The Treatment of Refractory Pituitary Adenomas
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Hidden hypercortisolism: a too frequently neglected clinical condition
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Endocrine Hypertension: A Practical Approach
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Recent Progress in the Medical Therapy of Pituitary Tumors
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Paraneoplastic Cushing syndrome, case-series and review of the literature
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An Individualized Approach to the Evaluation of Cushing Syndrome
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Medical management of Cushing's disease: When and how?
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Pharmacological Treatment of Cushing's Syndrome
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Radiotherapy as a tool for the treatment of Cushing’s disease
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Currently used and investigational drugs for Cushing´s disease
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Synergistic cortisol suppression by ketoconazole–osilodrostat combination therapy
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The Chinese guidelines for the diagnosis and treatment of pancreatic neuroendocrine neoplasms (2020)
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Glucocorticoids are active players and therapeutic targets in atherosclerotic cardiovascular disease
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Advances in the Medical Treatment of Cushing Disease
Tritos, N. A., & Biller, B. M. K. (2020) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2020.05.003 · Cited by 25 · see citing works
Medical Therapy for Cushing’s Syndrome in the Twenty-first Century
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MANAGEMENT OF ENDOCRINE DISEASE: Can we cure Cushing’s disease? A personal view
BERTAGNA, X. Y. (2018) · European Journal of Endocrinology · doi:10.1530/eje-18-0062 · Cited by 22 · see citing works
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What is the role of medical therapy in adrenal-dependent Cushing’s syndrome?
Braun, L. T., & Reincke, M. (2020) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2020.101376 · Cited by 21 · see citing works
Factors Affecting Dexamethasone Suppression Test Results
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Current and Emerging Medical Therapies in Pituitary Tumors
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Drug repurposing approach against chikungunya virus: an in vitro and in silico study
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Severe Cushing’s syndrome due to small cell prostate carcinoma: a case and review of literature
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Medical Management of Cushing Disease
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Update and Practical Recommendations for the Use of Medical Treatment of Cushing Syndrome
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Self-citationRegulation of the EGFR Pathway by HSP90 Is Involved in the Pathogenesis of Cushing’s Disease
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Advanced Adrenocortical Carcinoma: From Symptoms Control to Palliative Care
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- Authors
- Daniel, E., Aylwin, S., Mustafa, O., Ball, S., Munir, A., Boelaert, K., Chortis, V., Cuthbertson, D. J., Daousi, C., Rajeev, S. P., Davis, J., Cheer, K., Drake, W., Gunganah, K., Grossman, A., Gurnell, M., Powlson, A. S., Karavitaki, N., Huguet, I., Kearney, T., Mohit, K., Meeran, K., Hill, N., Rees, A., Lansdown, A. J., Trainer, P. J., Minder, A.-E. H., & Newell-Price, J.
- Affiliations
- University of Liverpool (GB)
- St Bartholomew's Hospital (GB)
- Corresponding author
- Newell-Price, John
- ORCID
- Daniel, Eleni
- Aylwin, Simon
- Mustafa, Omar
- Boelaert, Kristien
- Chortis, Vasileios
- Cuthbertson, Daniel J.
- Davis, Julian
- Drake, William
- Grossman, Ashley
- Gurnell, Mark
- Powlson, Andrew S.
- Karavitaki, Niki
- Huguet, Isabel
- Kearney, Tara
- Meeran, Karim
- Hill, Neil
- Rees, Aled
- Lansdown, Andrew J.
- Trainer, Peter J.
- Minder, Anna-Elisabeth H.
- Newell-Price, John
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2015-11
- Volume
- 100
- Issue
- 11
- Pages
- 4146-4154
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC5393433
- OpenAlex
- W2145652401
- Semantic Scholar
- be0aef20802f4f370e4b64b56cf53c0bf9ace992
- Cited by
- 231
- References
- 31
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 19 · 2023: 17 · 2022: 36 · 2021: 24 · 2020: 14 · 2019: 24 · 2018: 21 · 2017: 19 · 2016: 18 · 2015: 2
- FWCI
- 17.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- National Institute for Health and Care Research (ACF-2011-04-005)
- Society for Endocrinology
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Keywords
- metyrapone, Cushing's syndrome, hypercortisolism, Cushing's disease, ectopic ACTH syndrome, adrenocortical carcinoma, steroidogenesis inhibition, urinary free cortisol, treatment effectiveness, adverse effects, drug discontinuation, adrenal insufficiency
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Cushing Syndrome, Dose-Response Relationship, Drug, Drug Therapy, Combination, Enzyme Inhibitors, Humans, Hydrocortisone, Infant, Male, Metyrapone, Middle Aged, Pituitary Neoplasms, Retrospective Studies, Treatment Outcome, ACTH-Secreting Pituitary Adenoma, Young Adult
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